WO2019154859A1 - Inhibiteur de fap - Google Patents

Inhibiteur de fap Download PDF

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Publication number
WO2019154859A1
WO2019154859A1 PCT/EP2019/052912 EP2019052912W WO2019154859A1 WO 2019154859 A1 WO2019154859 A1 WO 2019154859A1 EP 2019052912 W EP2019052912 W EP 2019052912W WO 2019154859 A1 WO2019154859 A1 WO 2019154859A1
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WIPO (PCT)
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group
alkyl
cancer
virus
compound
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PCT/EP2019/052912
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English (en)
Inventor
Uwe Haberkorn
Anastasia LOKTEV
Thomas Lindner
Walter Mier
Dirk JÄGER
Niels Halama
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Universität Heidelberg
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Publication of WO2019154859A1 publication Critical patent/WO2019154859A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins

Definitions

  • the present invention relates to a compound, a liposome comprising said compound, a virus-like particle comprising said compound, a pharmaceutical composition comprising or consisting of said compound, said liposome or said virus-like particle, a kit comprising or consisting of said compound, said liposome, said virus-like particle or said pharmaceutical composition and use of the compound, liposome, virus-like particle or pharmaceutical composition in the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP).
  • FAP fibroblast activation protein
  • stroma may represent over 90% of the tumor mass in tumors with desmoplastic reaction such as breast, colon and pancreatic carcinoma.
  • CAFs cancer-associated fibroblasts
  • a distinguishing feature of CAFs is the expression of seprase or fibroblast activation protein a (FAP-a), a type II membrane bound glycoprotein belonging to the dipeptidyl peptidase 4 (DPP4) family.
  • FAP-a has both dipeptidyl peptidase and endopeptidase activity. The endopeptidase activity distinguishes FAP-a from the other members of the DPP4 family. Identified substrates for the endopeptidase activity so far are denatured Type I collagen, al- antitrypsin and several neuropeptides.
  • FAP-a has a role in normal developmental processes during embryogenesis and in tissue modelling. It is not or only at insignificant levels expressed on adult normal tissues. However, high expression occurs in wound healing, arthritis, artherosclerotic plaques, fibrosis and in more than 90% of epithelial carcinomas.
  • FAP-a in CAFs in many epithelial tumors and the fact that overexpression is associated with a worse prognosis in cancer patients led to the hypothesis that FAP-a activity is involved in cancer development as well as in cancer cell migration and spread. Therefore, the targeting of this enzyme for therapy can be considered as a promising strategy for the treatment of malignant tumors.
  • the present inventors developed a small molecule therapeutic based on a FAP-a specific inhibitor. Furthermore, the molecules can be used for the treatment of non-malignant diseases such as chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorders.
  • the present invention provides a compound of Formula (I)
  • Q, R, U, V, W, Y, Z are individually present or absent under the proviso that at least three of Q, R, U, V, W, Y, Z are present;
  • R 1 and R 2 are independently selected from the group consisting of -H, -OH, halo, Ci-6-alkyl, -
  • R 4 is selected from the group consisting of -H, -Ci-6-alkyl, -O-Ci-6-alkyl, -S-Ci-6-alkyl, aryl, and -Ci-6-aralkyl, each of said -Ci-6-alkyl being optionally substituted with from 1 to 3 substituents selected from -OH, oxo, halo and optionally connected to Q, R, U, V, W, Y or Z;
  • R 5 is selected from the group consisting of -H, halo and Ci-6-alkyl;
  • R 6 , and R 7 are independently selected from the group consisting of-H, an , under the proviso that R 6 and R 7 are not at the same time H,
  • D, A, E, and B are individually present or absent, preferably wherein at least A, E, and B are present, wherein when present:
  • D is a linker
  • A is selected from the group consisting of NR 4 , O, S, and CH 2 ;
  • E is selected from the group consisting of
  • i 1, 2, or 3;
  • j is 1, 2, or 3;
  • k is 1, 2, or 3;
  • n 1, 2, or 3;
  • B is selected from the group consisting of S, NR 4 , NR 4 -0, NR 4 -Ci-6-alkyl, NR 4 -Ci-6-alkyl-NR 4 , and a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein NR 4 -Ci-6-alkyl-NR 4 and the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of Ci-6-alkyl, aryl, Ci-6-aralkyl; and;
  • R 8 is selected from the group consisting a cytostatic and/or cytotoxic agent, a cytokine, an immunomodulatory molecule, an amphiphilic substance, polyglycolic acid, polylactic acid or a derivative thereof, a nucleic acid, a viral structural protein, a protein, biotin and combinations thereof; is a l-naphtyl moiety or a 5 to 10- membered N-containing aromatic or non aromatic mono- or bicyclic heterocycle, wherein there are 2 ring atoms between the N atom and X; said heterocycle optionally further comprising 1, 2 or 3 heteroatoms selected from O, N and S; and X is a C atom;
  • the present invention relates to a liposome comprising the compound of the first aspect.
  • the present invention relates to a virus-like particle (VLP) comprising the compound of the first aspect.
  • VLP virus-like particle
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, or the liposome of the second aspect, or the virus-like particle (VLP) of the third aspect, and, optionally, a pharmaceutically acceptable carrier and/or excipient.
  • VLP virus-like particle
  • the present invention relates to the compound of the first aspect, or the liposome of the second aspect, or the virus-like particle (VLP) of the third aspect, or the pharmaceutical composition of the fourth aspect for use in the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in an animal or a human subject.
  • FAP fibroblast activation protein
  • the present invention relates to a kit comprising or consisting of the compound of the first aspect, or the liposome of the second aspect, or the virus-like particle (VLP) of the third aspect, or the pharmaceutical composition of the second aspect and instructions for the treatment of a disease.
  • a kit comprising or consisting of the compound of the first aspect, or the liposome of the second aspect, or the virus-like particle (VLP) of the third aspect, or the pharmaceutical composition of the second aspect and instructions for the treatment of a disease.
  • VLP virus-like particle
  • Figure 1 In vitro characterization of 125 I-FAPI-01 and 177 Lu-FAPI-02.
  • FIG. 2 Binding specificity and relative internalization rates of FAPI derivatives.
  • A-C Binding and internalization rates of FAPI-03 to FAPI- 15 in relation to FAPI-02 (defined as 100%). Internalization rates after 1, 4 and 24 hrs of incubation are depicted in grey; the extracellular bound fraction is represented by the white bars.
  • D Binding of selected FAPI derivatives to HEK cells expressing murine FAP-a and human CD26 after 60 min of incubation. Right side : Ratio of muFAP to CD26 binding.
  • E Competitive binding of selected FAPI derivatives to HT-1080-FAP cells after adding increasing concentrations of unlabeled compound.
  • the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
  • alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl and alkynyl are provided.
  • alkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl, /so- propyl, butyl, /v -butyl, /er/-butyl, pentyl, hexyl, pentyl, or octyl.
  • Alkyl groups are optionally substituted.
  • heteroalkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, iso- propyl, butyl, v -butyl, sec-butyl, tert- butyl, pentyl, hexyl, pentyl, octyl, which is interrupted one or more times, e.g. 1 , 2, 3, 4, 5, with the same or different heteroatoms.
  • the heteroatoms are selected from O, S, and N, e.g.
  • Heteroalkyl groups are optionally substituted.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.
  • cycloalkyl and “heterocycloalkyl” are also meant to include bicyclic, tricyclic and polycyclic versions thereof.
  • heterocycloalkyl preferably refers to a saturated ring having five of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms.
  • “Cycloalkyl” and “heterocycloalkyl” groups are optionally substituted.
  • a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, l-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[2.2.l]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like.
  • heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diazo-spiro-[4,5] decyl, 1,7 diazo-spiro-[4,5] decyl, 1,6 diazo-spiro-[4,5] decyl, 2,8 diazo-spiro[4,5] decyl, 2,7 diazo-spiro[4,5] decyl, 2,6 diazo-spiro[4,5] decyl, 1,8 diazo-spiro-[5,4] decyl, 1,7 diazo-spiro- [5,4] decyl, 2,8 diazo-spiro-[5,4] decyl, 2,7 diazo-spiro[5,4] decyl, 3,8 diazo-spiro[5,4] decyl, 3,7 diazo-
  • aryl preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphtyl or anthracenyl. The aryl group is optionally substituted.
  • aralkyl refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above.
  • An example is the benzyl radical.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, /A -propyl, butyl, Ao-butyl, sec-butenyl, / ⁇ °r/-butyl, pentyl, hexyl, pentyl, octyl.
  • the aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.
  • heteroaryl preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1 , 2, 3, or 4 (for the five membered ring) or 1, 2, 3, 4, or 5 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13 , 14, 15 , or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S.
  • Examples are oxazolyl, isoxazolyl, l,2,5-oxadiazolyl, l,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, l,2,3-triazolyl, thiazolyl, isothiazolyl, l,2,3,-thiadiazolyl, l,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, l,2,3-triazinyl, l,2,4-triazinyl, l,3,5-triazinyl, l-benzofuranyl, 2- benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,l-benzosoxazoy
  • heteroarylkyl refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above.
  • An example is the 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g.
  • heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.
  • alkenyl and“cycloalkenyl” refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl.
  • the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g.
  • the cycloalkenyl ring comprises from 3 to 8 carbon atoms, i.e. 3, 4, 5, 6, 7, or 8, e.g.
  • alkynyl refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds.
  • An example is the propargyl radical.
  • the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, l-propynyl, 2- propynyl, l-butynyl, 2-butynyl, 3-butynyl, l-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.
  • carbon atoms or hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more elements selected from the group consisting of O, S, N or with groups containing one or more elements selected from the group consisting of O, S, N.
  • Embodiments include alkoxy, cycloalkoxy, arykoxy, aralkoxy, alkenyloxy, cycloalkenyloxy, alkynyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylamino, cycloalkylamino, arylamino, aralkylamino, alkenylamino, cycloalkenylamino, alkynylamino radicals.
  • hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more halogen atoms.
  • One radical is the trifluoromethyl radical.
  • radicals or two or more residues can be selected independently from each other, then the term“independently” means that the radicals or the residues may be the same or may be different.
  • a wording defining the limits of a range of length such as, e. g.,“from 1 to 6” means any integer from 1 to 6, i. e. 1, 2, 3, 4, 5 and 6.
  • any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
  • halo refers to a halogen residue selected from the group consisting of F, Br, I and Cl.
  • the halogen is F.
  • linker refers to any chemically suitable linker.
  • linker are not or only slowly cleaved under physiological conditions.
  • the linker does not comprise recognition sequences for proteases or recognition structures for other degrading enzymes.
  • the compounds of the invention are administered systemically to allow broad access to all compartments of the body and subsequently enrichment of the compounds of the invention wherever in the body the tumor is located, it is preferred that the linker is chosen in such that it is not or only slowly cleaved in blood. The cleavage is considered slowly, if less than 50% of the linkers are cleaved 2 h after administration of the compound to a human patient.
  • Suitable linkers comprises or consists of optionally substituted alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, aralkyl, heteroaralyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, sulfonyl, amines, ethers, thioethers phosphines, phosphoramidates, carboxamides, esters, imidoesters, amidines, thioesters, sulfonamides, 3-thiopyrrolidine-2,5-dion, carbamates, ureas, guanidines, thioureas, disulfides, oximes, hydrazines, hydrazides, hydrazones, diaza bonds, triazoles, triazolines, tetrazines, platinum complexes and amino acids, or
  • the linker can also be a cleavable linker such as a peptide motif that is cleaved by cathepsin. Any suitable linker that is cleavable by cathepsin can be used. Suitable cleavable peptide linkers are disclosed in Peterson et af, Bioconjugate Chem., 1998.
  • Suitable cleavable linkers comprises or consists of optionally substituted NC Tyr-Gln-Gly-Val-Gln-Phe- Lys(Aminobenzoyl), N02Tyr-Asn-Gly-Thr-Gly-Phe-Lys(Aminobenzoyl), NChTyr-Ser-Val- Val-Phe-Phe-Lys(Aminobenzoyl), NChTyr-Val-Gln-Ser-Ala-Phe, Multiple-Val-Gln-Phe-Val, NCteTyr-Gly-Val-Phe-Gln-Phe, N02Tyr-Gly-Thr-Val-Ala-Phe-Lys(Aminobenzoyl), NCteTyr- Ala-Thr-Ala-Phe-Phe-Lys(Aminobenzoyl), NChTyr-Gly-Ser-Val-Gln-P
  • N02Tyr-Val-Ala-Gln-Phe N02Tyr-Gln-Gly-Val-Gly-Phe-Lys(Aminobenzoyl), NCteTyr-Val- Asn-Asn-Asn-Phe-Lys(Aminobenzoyl), N02Tyr-Ala-Ser-Ala-Asn-Phe-Lys(Aminobenzoyl), N02Tyr-Phe-Gln-Thr-Gln-Phe-Lys(Aminobenzoyl), NChTyr-Ala-Ala-Ser-Phe-
  • N02Tyr-Val-Tyr-Tyr-Val-Phe NCkTyr-Ala-Ser-Tyr-Gly-Phe, Z-Phe-Lys-PABC, Z-Phe-Lys, Z-Val-Lys-PABC, Z-Ala-Lys-P ABC , Phe-Phe-Lys-PABC, D-Phe-Phe-Lys-PABC, D-Ala- Phe-Lys-PABC, Gly-Phe-Lys-PABC, Ac-Phe-Lys-PABC, HCO-Phe-Lys-PABC, Phe-Lys- PABC, Z-Lys-PABC, Z-Val-Cit-PABC, Z-Val-Cit, Z-Phe-Cit-PABC, Z-Leu-Cit-PABC, Z-Ile- Cit-PABC, Z-Trp-Cit-PABC, Z-Phe-Arg
  • amino acid refers to any organic acid containing one or more amino substituents, e.g. a-, b- or g-amino, derivatives of aliphatic carboxylic acids.
  • amino substituents e.g. a-, b- or g-amino, derivatives of aliphatic carboxylic acids.
  • polypeptide notation e.g. Xaa5, i.e. XaalXaa2Xaa3Xaa4Xaa5
  • Xaal to Xaa5 are each and independently selected from amino acids as defined
  • the left hand direction is the amino terminal direction
  • the right hand direction is the carboxy terminal direction, in accordance with standard usage and convention.
  • conventional amino acid refers to the twenty naturally occurring amino acids, and encompasses all stereomeric isoforms, i.e. D,L-, D- and L-amino acids thereof. These conventional amino acids can herein also be referred to by their conventional three- letter or one-letter abbreviations and their abbreviations follow conventional usage (see, for example, Immunology— A Synthesis, 2nd Edition, E. S. Golub and D. R. Gren, Eds., Sinauer Associates, Sunderland Mass. (1991)).
  • non-conventional amino acid refers to unnatural amino acids or chemical amino acid analogues, e.g. a,a-disubstituted amino acids, N-alkyl amino acids, homo-amino acids, dehydroamino acids, aromatic amino acids (other than phenylalanine, tyrosine and tryptophan), and ortho-, meta- or para-aminobenzoic acid.
  • Non-conventional amino acids also include compounds which have an amine and carboxyl functional group separated in a 1,3 or larger substitution pattern, such as b-alanine, g-amino butyric acid, Freidinger lactam, the bicyclic dipeptide (BTD) , amino-methyl benzoic acid and others well known in the art.
  • BTD bicyclic dipeptide
  • Statine- like isosteres, hydroxyethylene isosteres, reduced amide bond isosteres, thioamide isosteres, urea isosteres, carbamate isosteres, thioether isosteres, vinyl isosteres and other amide bond isosteres known to the art may also be used.
  • analogues or non-conventional amino acids may improve the stability and biological half-life of the added peptide since they are more resistant to breakdown under physiological conditions.
  • the person skilled in the art will be aware of similar types of substitution which may be made.
  • a non-limiting list of non- conventional amino acids which may be used as suitable building blocks for a peptide and their standard abbreviations (in brackets) is as follows: a-aminobutyric acid (Abu), L-N- methylalanine (Nmala), a-amino-a-methylbutyrate (Mgabu), L-N-methylarginine (Nmarg), aminocyclopropane (Cpro), L-N-methylasparagine (Nmasn), carboxylate L-N-methylaspartic acid (Nmasp), aniinoisobutyric acid (Aib), L-N-methylcysteine (Nmcys), aminonorbomyl (Norb), L-N-methylglutamine
  • cytotoxic effect refers to the depletion, elimination and/or the killing of a target cell(s).
  • cyctotoxic agent refers to an agent that has a cytotoxic and/or cytostatic effect on a cell.
  • the term is intended to include chemotherapeutic agents, and toxins such as enzymatically active toxins of bacterial, fungal, plant, or animal origin, and fragments thereof.
  • cytostatic effect refers to the inhibition of cell proliferation.
  • cytostatic agent refers to an agent that has a cytostatic effect on a cell, thereby inhibiting the growth and/or expansion of a specific subset of cells.
  • cytokine refers to small proteins ( ⁇ 5-20 kDa) that are involved in autocrine signalling, paracrine signalling and endocrine signalling as immunomodulating agents. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors but generally not hormones or growth factors.
  • immunomodulatory molecule refers to substance that stimulates or suppresses the immune system and may help the body fight cancer, infection, or other diseases.
  • Specific immunomodulating molecules can be monoclonal antibodies, cytokines, and vaccines, which affect specific parts of the immune system.
  • amphiphilic substance refers to compounds with both hydrophilic and lipophilic properties. Common amphiphilic substances are phospholipids, cholesterol, glycolipids, fatty acids, bile acids, saponins, pepducins, local anaesthetics, Ab proteins and antimicrobial peptides.
  • protein and polypeptide are used interchangeably herein and refer to any peptide -bond-linked chain of amino acids, regardless of length or post-translational modification.
  • the amino acid is any of the above-defined amino acids.
  • Proteins usable in the present invention can be further modified by chemical modification. This means such a chemically modified polypeptide comprises other chemical groups than the 20 naturally occurring amino acids. Examples of such other chemical groups include without limitation glycosylated amino acids and phosphorylated amino acids. Chemical modifications of a polypeptide may provide advantageous properties as compared to the parent polypeptide, e.g. one or more of enhanced stability, increased biological half-life, or increased water solubility.
  • N-containing aromatic or non-aromatic mono or bicyclic heterocycle refers to a cyclic saturated or unsaturated hydrocarbon compound which contains at least one nitrogen atom as constituent of the cyclic chain.
  • nucleic acid and the term“polynucleotide” are used interchangeably herein and refer to polymeric or oligomeric macromolecules, or large biological molecules, essential for all known forms of life.
  • Nucleic acids which include DNA (deoxyribonucleic acid) and RNA (ribonucleic acid), are made from monomers known as nucleotides. Most naturally occurring DNA molecules consist of two complementary biopolymer strands coiled around each other to form a double helix. The DNA strand is also known as polynucleotides consisting of nucleotides.
  • Each nucleotide is composed of a nitrogen-containing nucleobase as well as a monosaccharide sugar called deoxyribose or ribose and a phosphate group.
  • Naturally occurring nucleobases comprise guanine (G), adenine (A), thymine (T), uracil (U) or cytosine (C).
  • the nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. If the sugar is desoxyribose, the polymer is DNA. If the sugar is ribose, the polymer is RNA.
  • nucleic acid includes but is not limited to ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and mixtures thereof such as e.g. RNA-DNA hybrids (within one strand), as well as cDNA, genomic DNA, recombinant DNA, cRNA and mRNA.
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • a nucleic acid may consist of an entire gene, or a portion thereof, the nucleic acid may also be a miRNA, siRNA, piRNA or shRNA.
  • MiRNAs are short ribonucleic acid (RNA) molecules, which are on average 22 nucleotides long but may be longer and which are found in all eukaryotic cells, i.e. in plants, animals, and some viruses, which functions in transcriptional and post-transcriptional regulation of gene expression.
  • MiRNAs are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts (mRNAs), usually resulting in translational repression and gene silencing.
  • mRNAs target messenger RNA transcripts
  • siRNAs sometimes known as short interfering RNA or silencing RNA, are short ribonucleic acid (RNA molecules), between 20 - 25 nucleotides in length.
  • RNA interference RNA interference
  • shRNA short hairpin RNA
  • shRNA small hairpin RNA
  • RNAi RNA interference
  • Expression of shRNA in cells is typically accomplished by delivery of plasmids or through viral or bacterial vectors.
  • PiRNAs are also short RNAs which usually comprise 26 - 31 nucleotides and derive their name from so-called piwi proteins they are binding to.
  • the nucleic acid can also be an artificial nucleic acid.
  • Artificial nucleic acids include polyamide or peptide nucleic acid (PNA), morpholino and locked nucleic acid (LNA), as well as glycol nucleic acid (GNA) and threose nucleic acid (TNA). Each of these is distinguished from naturally-occurring DNA or RNA by changes to the backbone of the molecule.
  • the nucleic acids can e.g. be synthesized chemically, e.g. in accordance with the phosphotriester method (see, for example, Uhlmann, E. & Peyman, A. (1990) Chemical Reviews, 90, 543-584).
  • VSP viral structural protein
  • VCP viral coat proteins
  • VAG viral envelope glycoproteins
  • VCP viral coat protein
  • a structural virus capsid protein of a virus Preferably the virus is a double-stranded DNA virus, single-stranded DNA virus, double-stranded RNA virus, single-stranded RNA virus, negative-sense single-stranded RNA virus, single-stranded RNA reverse transcribing virus, double-stranded RNA reverse transcribing virus.
  • the VCP can comprise major capsid proteins of adeno-associated virus (AAV).
  • AAV adeno-associated virus
  • viral envelope glycoproteins are used in the context of the present invention to refer to viral proteins that are part of the viral envelope.
  • the viral envelope is typically derived from portions of the host cell membrane, e.g. comprises phospholipids, and additionally comprise viral glycoproteins that, e.g. help the virus to avoid the immune system.
  • Enveloped viruses comprise DNA viruses, in particular Herpesviruses, Poxviruses, and Hepadnaviruses; RNA viruses, in particular Flavivirus, Togavirus, Coronavirus, Hepatitis D, Orthomyxovirus, Paramyxovirus, Rhabdovirus, Bunyavirus, Filovirus and Retroviruses. Accordingly, the viral envelop glycoprotein is preferably derived from any of these viruses.
  • Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of choline or derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sul
  • Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula (I).
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • esters for example, methyl, ethyl
  • cycloalkyl for example, cyclohexyl
  • aralkyl for example, benzyl, p- methoxybenzyl
  • alkylcarbonyloxyalkyl for example, pivaloyloxymethyl
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers.
  • EP 0 039 051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • Compounds according to the invention can be synthesized according to one or more of the following methods. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for example, by inversion.
  • Certain compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-l25 ( 125 I) or carbon-l4 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • liposome refers to uni- or multilame llar (preferably 2, 3, 4, 5, 6, 7, 8, 9, and 10 lamellar) lipid structures enclosing an aqueous interior, depending on the number of lipid membranes formed.
  • Lipids, which are capable of forming a liposomes include all substances having fatty or fat-like properties. Such lipids comprise an extended apolar residue (X) and usually a water soluble, polar, hydrophilic residue (Y), which can be characterized by the basic formula
  • n 0
  • Preferred lipids, which can make up the lipids in the liposomes of the present invention are selected from the group consisting of glycerides, glycerophospholipides, glycerophosphinolipids, glycerophosphonolipids, sulfolipids, sphingolipids, phospholipids, isoprenolides, steroids, stearines, steroles and carbohydrate containing lipids.
  • a virus like particle is a multimer of VSP, preferably of VCPs and/or VEPs that does not comprise polynucleotides but which otherwise has properties of a virus, e.g. binds to cell surface receptors, is internalized with the receptor, is stable in blood, and/or comprises glycoproteins etc.
  • VLPs are typically assembled of multimers of VCPs and/or VEPs, in particular of VCPs.
  • VLPs are well known in the art and have been produced from a number of viruses including Parvoviridae (e.g. adeno-associated virus), Retroviridae (e.g. HIV), Flaviviridae (e.g. Hepatitis C virus) and bacteriophages (e.g. QP, AP205).
  • composition refers to a substance and/or a combination of substances being used for the identification, prevention or treatment of a tissue status or disease.
  • the pharmaceutical composition is formulated to be suitable for administration to a patient in order to prevent and/or treat disease.
  • a pharmaceutical composition refers to the combination of an active agent with a carrier, inert or active, making the composition suitable for therapeutic use.
  • Pharmaceutical compositions can be formulated for oral, parenteral, topical, inhalative, rectal, sublingual, transdermal, subcutaneous or vaginal application routes according to their chemical and physical properties.
  • Pharmaceutical compositions comprise solid, semisolid, liquid, transdermal therapeutic systems (TTS).
  • Solid compositions are selected from the group consisting of tablets, coated tablets, powder, granulate, pellets, capsules, effervescent tablets or transdermal therapeutic systems. Also comprised are liquid compositions, selected from the group consisting of solutions, syrups, infusions, extracts, solutions for intravenous application, solutions for infusion or solutions of the carrier systems of the present invention.
  • Semisolid compositions that can be used in the context of the invention comprise emulsion, suspension, creams, lotions, gels, globules, buccal tablets and suppositories.
  • “Pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • a saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin.
  • Fibroblast activation protein is also known under the term“seprase”. Both terms can be used interchangeably herein.
  • Fibroblast activation protein is a homodimeric integral protein with dipeptidyl peptidase IV (DPPIV)-like fold, featuring an alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain.
  • DPPIV dipeptidyl peptidase IV
  • the present invention provides a compound of Formula (I)
  • Q, R, U, V, W, Y, Z are individually present or absent under the proviso that at least three of Q, R, U, V, W, Y, Z are present;
  • R 1 and R 2 are independently selected from the group consisting of -H, -OH, halo, Ci-6-alkyl, - O-Ci-6-alkyl, S-Ci-e-alkyl;
  • R 4 is selected from the group consisting of -H, -Ci-6-alkyl, -O-Ci-6-alkyl, -S-Ci-6-alkyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, aryl, and -Ci-6-aralkyl, each of said - Ci-6-alkyl being optionally substituted with from 1 to 3 substituents selected from -OH, oxo, halo and optionally connected to Q, R, U, V, W, Y or Z;
  • R 5 is selected from the group consisting of -H, halo and Ci-6-alkyl
  • R 6 , and R 7 are independently selected from the group consisting of-H, . under the proviso that R 6 and R 7 are not at the same time H, preferably R 6 is attached to the 7- or 8-quinolyl position and R 7 is attached to the 5- or 6- quinolyl position; more preferably R 6 is attached to the 7-quinolyl position and R 7 is attached to the 6-quinolyl position,
  • D, A, E, and B are individually present or absent, preferably wherein at least A, E, and B are present, wherein when present:
  • D is a linker
  • A is selected from the group consisting of NR 4 , O, S, and CEb;
  • E is selected from the group consisting of
  • i 1, 2, or 3;
  • j is 1, 2, or 3;
  • k is 1, 2, or 3;
  • n 1, 2, or 3;
  • E is Ci-6-alkyl, most preferably, E is C3 or C4 alkyl;
  • B is selected from the group consisting of S, NR 4 , NR 4 -0, NR 4 -Ci-6-alkyl, NR 4 -Ci-6-alkyl-NR 4 , and a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein NR 4 -Ci-6-alkyl-NR 4 and the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of Ci-6-alkyl, aryl, Ci-6-aralkyl; and
  • R 8 is selected from the group consisting of a cytostatic and/or cytotoxic agent, a cytokine, an immunomodulatory molecule, an amphiphilic substance, polyglycolic acid, polylactic acid or a derivative thereof a nucleic acid, a viral structural protein, a protein, biotin and combinations thereof; is a l-naphtyl moiety or a 5 to 10- membered N-containing aromatic or non- aromatic mono- or bicyclic heterocycle, wherein there are 2 ring atoms between the N atom and X; said heterocycle optionally further comprising 1, 2 or 3 heteroatoms selected from O, N and S; and X is a C atom;
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • Q, R, U are CH 2 and are individually present or absent; preferably, Q and R are absent;
  • W is NR 4 ; preferably, W is NH;
  • Y is HCR 4 ; preferably, Y is CH 2 ; and
  • V is CH 2 ;
  • W is NH
  • Y is CH 2 ;
  • R 1 and R 2 are independently selected from the group consisting of -H and halo; preferably, R 1 and R 2 are halo; more preferably, R 1 and R 2 are F;
  • R 3 is selected from the group consisting of -H, -CN, and -B(OH) 2 ; preferably, R 3 is -CN or - B(OH) 2 ; more preferably, R 3 is -CN; R 4 is selected from the group consisting of -H and -Ci-6-alkyl, wherein the -Ci-6-alkyl is optionally substituted with from 1 to 3 substituents selected from -OH.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert- butyl, pentyl and hexyl.
  • V is CH 2 ;
  • W is NH
  • Y is CH 2 ;
  • R 1 and R 2 are independently selected from the group consisting of -H and halo; preferably, R 1 and R 2 are halo; more preferably, R 1 and R 2 are F;
  • R 3 is selected from the group consisting of -H, -CN, and -B(OH) 2 ; preferably, R 3 is -CN or - B(OH) 2 ; more preferably, R 3 is -CN;
  • R 4 is selected from the group consisting of -H and -Ci-6-alkyl, wherein the -Ci-6-alkyl is optionally substituted with from 1 to 3 substituents selected from -OH.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert- butyl, pentyl and hexyl.
  • V is CH 2 ;
  • W is CH 2 ;
  • Y is NH
  • R 1 and R 2 are independently selected from the group consisting of -H and halo; preferably, R 1 and R 2 are halo; more preferably, R 1 and R 2 are F;
  • R 3 is selected from the group consisting of -H, -CN, and -B(OH) 2 ; preferably, R 3 is -CN or - B(OH) 2 ; more preferably, R 3 is -CN;
  • R 4 is selected from the group consisting of -H and -Ci-6-alkyl, wherein the -Ci-6-alkyl is optionally substituted with from 1 to 3 substituents selected from -OH.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert- butyl, pentyl and hexyl.
  • optionally ffurther comprising 1 or 2 heteroatoms selected from O, N, and S.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is absent or is present and is a cleavable linker such as a peptide motif that is cleaved by cathepsin;
  • A is O
  • E is Ci- 6 -alkyl or , wherein m is 1, 2, or 3;
  • Ci- 6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is Ci- 6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -Ci- 6 -alkyl or a 5- to lO-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of Ci- 6 -alkyl, aryl, Ci-6-aralkyl.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is absent or is present and is a cleavable linker such as a peptide motif that is cleaved by cathepsin;
  • A is S
  • E is Ci-6-alkyl or , wherein m is 1, 2, or 3;
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is Ci-6-alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -Ci-6-alkyl or a 5- to lO-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of Ci-6-alkyl, aryl, Ci-6-aralkyl.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is absent or is present and is a cleavable linker such as a peptide motif that is cleaved by cathepsin;
  • A is CEE
  • E is Ci-6-alkyl or , wherein m is 1, 2, or 3;
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is Ci-6-alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -Ci-6-alkyl or a 5- to lO-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of Ci-6-alkyl, aryl, Ci-6-aralkyl.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R is , preferably R is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is absent or is present and is a cleavable linker such as a peptide motif that is cleaved by cathepsin;
  • A is NH
  • E is Ci-6-alkyl or , wherein m is 1, 2, or 3;
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is Ci-6-alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -Ci-6-alkyl or a 5- to lO-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of Ci-6-alkyl, aryl, Ci-6-aralkyl.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is an amino acid, preferably carrying a charged side chain
  • A is O
  • E is Ci-6-alkyl or , wherein m is 1, 2, or 3;
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is Ci-6-alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -Ci-6-alkyl or a 5- to lO-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of Ci-6-alkyl, aryl, Ci-6-aralkyl.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is an amino acid, preferably carrying a charged side chain
  • A is S
  • E is Ci-6-alkyl or , wherein m is 1, 2, or 3;
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is Ci-6-alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -Ci-6-alkyl or a 5- to lO-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of Ci-6-alkyl, aryl, Ci-6-aralkyl.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H; 7
  • R is , preferably R is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is an amino acid, preferably carrying a charged side chain;
  • A is CEE;
  • E is Ci-6-alkyl or , wherein m is 1, 2, or 3;
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is Ci-6-alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -Ci-6-alkyl or a 5- to lO-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of Ci-6-alkyl, aryl, Ci-6-aralkyl.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R is , preferably R is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is an amino acid, preferably carrying a charged side chain
  • A is NH
  • E is Ci-6-alkyl or , wherein m is 1, 2, or 3;
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is Ci-6-alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -Ci-6-alkyl or a 5- to lO-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of Ci-6-alkyl, aryl, Ci-6-aralkyl.
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is absent or is present and is a cleavable linker such as a peptide motif that is cleaved by cathepsin;
  • A is O
  • E is Ci-6-alkyl or , wherein m is 1, 2, or 3;
  • E is C 1-6- alkyl and Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is Ci-6-alkyl, most preferably, E is C3 or C4 alkyl;
  • B is a 5- to lO-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 nitrogen atoms.
  • R 5 and R 6 are H
  • R is , preferably R is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is absent or is present and is a cleavable linker such as a peptide motif that is cleaved by cathepsin;
  • A is O
  • E is C3 or C4 alkyl; more preferably, E is propyl or butyl;
  • B is a 5- to lO-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 nitrogen atoms.
  • the N-containing heterocycle comprised in B is an aromatic or non-aromatic monocyclic heterocycle:
  • the heterocycle optionally further comprises 1 or 2 heteroatoms selected form O, N and S, optionally further comprises 1 nitrogen;
  • 1 is 1 or 2.
  • the N-containing heterocycle comprised in B is selected from the group consisting of:
  • the heterocycle optionally further comprises 1 or 2 heteroatoms selected from O, N and S, optionally further comprises 1 nitrogen, optionally compromises one or more (e.g. amino acid derived) side chains;
  • I 1 is attached to position 1, 2, or 3, preferably to position 2;
  • o 1 or 2;
  • the N-containing heterocycle comprised in B is preferably, if the N-containing heterocycle comprised in B is , the N-
  • containing heterocycle comprised in B is selected from the group consisting of
  • the N-containing heterocycle comprised in B is selected from the group consisting of:
  • R 5 and R 6 are H
  • R 7 is . preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is absent or is present and is a cleavable linker such as a peptide motif that is cleaved by cathepsin;
  • A is O
  • E is propyl or butyl
  • W is NH
  • Y is CH 2 ;
  • R 1 and R 2 are independently selected from the group consisting of -H and halo; preferably, R 1 and R 2 are independently selected from the group consisting of -H and F; more preferably, R 1 and R 2 are the same and are selected from the group consisting of -H and F;
  • R 3 is -CN
  • R 5 and R 6 are H
  • R 7 is . preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is absent or is present and is a cleavable linker such as a peptide motif that is cleaved by cathepsin;
  • A is O
  • E is Ci- 6 -alkyl or , wherein m is 1, 2, or 3; preferably, E is Ci- 6 - alkyl; preferably, Ci- 6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i- propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is Ci-6-alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NH-Ci-e-alkyl
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl,
  • W is NH
  • Y is CEE
  • R 1 and R 2 are the same and are selected from the group consisting of -H and F;
  • R 3 is -CN
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is absent or is present and is a cleavable linker such as a peptide motif that is cleaved by cathepsin;
  • A is O
  • E is methyl, ethyl, propyl or butyl
  • W is NH
  • Y is CH 2 ;
  • R 1 and R 2 are the same and are selected from the group consisting of -H and F;
  • R 3 is -CN
  • R 5 and R 6 are H
  • R is , R is attached to the 6-quinolyl position, wherein
  • D is absent or is present and is a cleavable linker such as a peptide motif that is cleaved by cathepsin;
  • A is O
  • E is methyl, ethyl, propyl or butyl
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert- butyl, pentyl and hexyl.
  • Ci-6-aralkyl is selected from the group consisting of benzyl, phenyl-ethyl, phenyl-propyl, and phenyl-butyl.
  • the compound of the first aspect of the invention is selected from the compounds of table 1. More preferably, the compound of the first aspect of the invention is selected from the group consisting of FAPI-02 and F API-04.
  • Table 1 Preferred compounds of the first aspect of the invention.
  • R 8 is a cytostatic and/or cytotoxic agent.
  • the cytostatic and/or cytotoxic agent is selected from the group consisting of alkylating substances, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-estrogens, platinum compounds, hormones and antihormones, interferons and inhibitors of cell cycle-dependent protein kinases (CDKs), inhibitors of cyclooxygenases and/or lipoxygenases, biogeneic fatty acids and fatty acid derivatives, including prostanoids and leukotrienes, inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkylsulfonates,
  • the cytostatic and/or cytotoxic agent is selected from the group consisting of doxorubicin, a-amanitin and monomethyl auristatin E.
  • R 8 is doxorubicin.
  • R 8 is a cytokine.
  • the cytokine is a chemokine molecule.
  • the chemokine molecule is selected from the group consisting of CXCL9, CXCL10 and CX3CL1.
  • R 8 is CXCL9.
  • R 8 is CXCL10.
  • R 8 is CX3CL1.
  • R 8 is an immunomodulatory molecule.
  • the immunomodulatory molecule is selected from the group consisting of CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL1, CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, interleukin-2, interferon alpha and interferon gamma. More preferably, the immunomodulatory molecule is selected from the group consisting of CXCL1, CXCL2, CXCL3,
  • R 8 is an amphiphilic substance.
  • the amphiphilic substance is selected from the group consisting of a lipid, a phospholipid and other highly lipophilic moiety conjugated to a polar group such as an ammonium ion or inositol triphosphate.
  • the lipid is selected from the group consisting of saccharolipids, prenol lipids, sterol lipids, glycerolipids, polyketides and fatty acids
  • the phospholipid is selected from the group consisting of plasmalogens, sphingo lipids, phophatidates and phosphoinositides.
  • the amphiphilic substance is a lipid or a phospholipid.
  • the amphiphilic substance is N- PEGylated l,2-disteaorylglycero-3-phosphoethanolamine.
  • R 8 is a lipid.
  • R 8 is a phospholipid.
  • R 8 is /V-PEGylatcd l,2-disteaorylglycero-3- phosphoethanolamine.
  • R 8 is a nucleic acid.
  • the nucleic acid is selected from the group consisting of DNA, RNA, siRNA, mRNA, PNA and cDNA. More preferably, the nucleic acid encodes a cytokine and/or an immunomodulatory molecule as defined above. More preferably, the nucleic acid is a siRNA or PNA.
  • R 8 is a viral structural protein.
  • the viral structural protein is of a virus selected from the group consisting of
  • Myoviridae preferably Myoviridae, Siphoviridae, Podoviridae, Herpesviridae, Adenoviridae, Baculoviridae, Papillomaviridae, Polydnaviridae, Polyomaviridae, Poxviridae;
  • RNA virus preferably Coronaviridae, Picomaviridae, Caliciviridae, Togaviridae, Flaviviridae, Astroviridae, Arteriviridae, Hepeviridae;
  • Arenaviridae preferably Arenaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Bunyaviridae, Orthomyxoviridae, Bomaviridae;
  • the viral structural protein preferably VCP is derived from a virus selected from the group consisting of double-stranded DNA virus, preferably Myoviridae, Siphoviridae, Podoviridae, Herpesviridae, Adenoviridae, Baculoviridae, Papillomaviridae, Polydnaviridae, Polyomaviridae, Poxviridae; single-stranded DNA virus, preferably Anelloviridae, Inoviridae, Parvoviridae; double-stranded RNA virus, preferably Reoviridae; single-stranded RNA virus, preferably Coronaviridae, Picomaviridae, Caliciviridae, Togaviridae, Flaviviridae, Astroviridae, Arteriviridae, Hepeviridae; negative-sense single- stranded RNA vims, preferably Arenaviridae, Filoviridae, Para
  • the VCP is from a family of the Parvoviridae, preferably from adeno-associated vims.
  • the AAV is human AAV, bovine AAV, caprine AAV, avian AAV, canine parvovirus (CPV), mouse parvovirus; minute vims of mice (MVM); parvovirus B19 (B19); parvovirus Hl (Hl); human bocavims (HBoV); feline panleukopenia vims (FPV); or goose parvovirus (GPV).
  • the VCP is from a certain AAV-serotype, preferably AAV-l, AAV-2, AAV-2- AAV-3 hybrid, AAV-3a, AAV-3b, AAV-4, AAV-5, AAV-6, AAV-6.2, AAV-7, AAV-8, AAV-9, AAV-10, AAVrh.lO, AAV-l 1, AAV-12, AAV-13 or AAVrh32.33. More preferably, the VCP is from AAV-2 or a variant thereof that is capable of assembling into a VLP.
  • R 8 is protein, wherein the protein is selected from the group consisting of a membrane bound protein and unbound protein.
  • the protein include but are not limited to CEA, CA19-9, Macrophage Migration Inhibition Factor (MIF), IL-8 (interleukin 8), AXL, MER and c-MET.
  • R 8 is biotin.
  • the present invention relates to a liposome comprising or consisting of the compound of the first aspect, wherein R 8 is an amphiphilic substance.
  • the liposomes of the present invention can be various types of liposomes, for example, as described in Alavi et ah, Adv Pharm Bull, 2017.
  • the liposomes of the present invention is a stealth liposome.
  • Stealth liposomes are well known in the art and are for example reviewed by Immordino et al., Int J Nanomedicine, 2006.
  • the liposome of the present invention can be positively charged, negatively charged or neutral liposomes.
  • the charge of a liposome is determined by the lipid composition and is the average of all charges of the lipids comprised in the liposome. For example, a mixture of a negatively charged phospholipid and cholesterol will yield a negatively charged liposome.
  • Preferred lipids/phospholipids to be used in liposomes include but are not limited to glycerides, glycerophospholipides, glycerophosphinolipids, glycerophosphonolipids, sulfolipids, sphingolipids, phospholipids, isoprenolides, steroids, stearines, steroles and carbohydrate containing lipids.
  • the negatively charged lipid/phospholipid is selected from the group consisting of phosphatidylserine (PS), phosphatidylglycerol (PG) and phosphatidic acid (PA).
  • PS and PG are collective terms for lipids sharing a similar phosphatidylserine and phosphatidylglycerol, respectively, head group.
  • many different apolar residues can be attached to these head groups.
  • PSs and PGs isolated from different natural sources vary substantially in the length, composition and/or chemical structure of the attached apolar residues and naturally occurring PS and PG usually is a mixture of PSs and PGs with different apolar residues.
  • the PS employed in the liposomes of the present invention is preferably selected from the group consisting of palmitoyloleoylphosphatidylserine, palmitoyllinoeoyl- phosphatidylserine, palmitoylarachidonoylphosphatidylserine, palmitoyldocosahexaenoyl- phosphatidylserine, stearoyloleoylphosphatidylserine, stearoyllinoleoylphosphatidylserine, stearoyl-arachidonoylphosphatidylserine, stearoyldocosahexaenoylphosphatidylserine, dicaprylphosphatidylserine, dilauroylphosphatidylserine, dimyristoylphosphatidylserine, diphytanoylphosphatidylserine, di
  • the PG employed in the liposome of the present invention is preferably selected from the group consisting of palmitoyloleoylphosphatidylglycerol, palmitoyl- linoleoylphosphatidylglycerol, palmitoylarachidonoylphosphatidylglycerol, palmitoyl- docosahexaenoylphosphatidylglycerol, stearoyloleoylphosphatidylglycerol, stearoyl- linoleoylphosphatidylglycerol, stearoylarachidonoylphosphatidylglycerol, stearoyldocosa- hexaenoylphosphatidylglycerol, dicaprylphosphatidylglycerol dilauroylphosphatidylglycerol, diheptadecanoylphosphatidylglycerol
  • PE is also a generic term for lipids sharing a phosphatidylethanolamine head group.
  • the PE is selected from the group consisting of palmitoyloleoylphosphatidylethanolamine, palmitoyllinoleoylphosphatidylethanolamine, palmitoylarachidonoylphosphatidylethanolamine, palmitoyldocosahexaenoylphosphatidyl- ethanolamine, stearoyloleoylphosphatidylethanolamine, stearoyllinoleoylphosphatidyl- ethanolamine, stearoylarachidonoylphosphatidylethanolamine, stearoyldocosahexaenoyl- phosphatidylethanolamine, dilauroylphosphatidylethanolamine, dimyristoylphosphatidyl- ethanolamine, diphytanoylphosphatidylethanolamine
  • the liposome of the present invention can comprise at least one further component selected from the group consisting of an adjuvant, additive, and auxiliary substance.
  • adjuvants are selected from the group consisting of unmethylated DNA, in particular unmethylated DNA comprising CpG dinucleotides (CpG motif), in particular CpG ODN with phosphorothioate (PTO) backbone (CpG PTO ODN) or phosphodiester (PO) backbone (CpG PO ODN); bacterial products from the outer membrane of Gram-negative bacteria, in particular monophosphoryl lipid A (MPLA), lipopolysaccharides (LPS), muramyl dipeptides and derivatives thereof; synthetic lipopeptide derivatives, in particular Par Cys; lipoarabino- mannan; peptidoglycan; zymosan; heat shock proteins (HSP), in particular HSP 70; dsRNA and synthetic derivatives thereof, in particular Poly Epoly C; polycationic peptides, in particular poly-L
  • Particular preferred adjuvants which can be comprised in the liposome of the present invention are selected from the group unmethylated DNA, in particular unmethylated DNA comprising CpG dinucleotides (CpG motif), in particular CpG ODN with phosphorothioate (PTO) backbone (CpG PTO ODN) or phosphodiester (PO) backbone (CpG PO ODN), bacterial products from the outer membrane of Gram-negative bacteria, in particular monophosphoryl lipid A (MPLA) and synthetic lipopeptide derivatives, in particular Par Cys.
  • CpG motif CpG dinucleotides
  • PTO phosphorothioate
  • PO phosphodiester
  • MPLA monophosphoryl lipid A
  • synthetic lipopeptide derivatives in particular Par Cys.
  • additive comprises substances, which stabilize any component of the liposome or of the liquid medium like, for example, antioxidants, radical scavengers or the like.
  • stabilizers are selected from the group consisting of a-tocopherol or carbohydrates, in particular glucose, sorbitol, sucrose, maltose, trehalose, lactose, cellubiose, raffmose, maltotriose, or dextran.
  • the stabilizers can be comprised in the lipid membranes of the liposomes, the interior of the liposomes and/or within the liquid medium surrounding the liposomes.
  • Liposomes of the present invention can have a diameter between 10 and 1000 nm. They, however, have in a preferred embodiment a diameter of between 30 and 800 nm, preferably between 40 and 500 nm, preferably between 50 and 300 nm, and more preferably between 100 and 200 nm.
  • the diameter of the liposomes can be affected, for example, by extrusion of the liposomal composition through sieves or meshes with a known pore size. This and further methods of controlling the size of liposomes are well known in the art and are described, for example, in Mayhew et al. (1984) Biochim. Biophys. Acta 775: 169-174 or Olson et al. (1979) Biochim. Biophys. Acta 557:9-23.
  • the liposome or the mixture of liposomes of the present invention are comprised in a liquid medium.
  • liquid medium preferably comprises all biocompatible, physiological acceptable liquids and liquid compositions in particular FLO, aqueous salt solutions, and buffer solutions like, for example, PBS, Ringer solution and the like.
  • the liposome is loaded with a substance selected from the group consisting of an agent and a nucleic acid.
  • the agent that the liposome is loaded with preferably is a cytostatic and/or cytotoxic agent as disclosed above.
  • the nucleic acid that the liposome is loaded with preferably is a nucleic acid as disclosed above.
  • a variety of methods are available in the prior art to "load" a liposome with a given therapeutic agent. In its simplest form the therapeutic agent(s) is(are) admixed with the lipid components during formation of the liposomes. Other passive loading methods include dehydration-rehydration (Kirby & Gregoriadis (1984) Biotechnology 2:979), reverse-phase evaporation (Szoka & Papahadjopoulos (1978) Proc. Natl.Acad. Sci.
  • the present invention relates to a virus-like particle (VLP) comprising or consisting of the compound of the first aspect of the present invention, wherein R 8 is a viral structural protein.
  • VLP virus-like particle
  • the virus-like particle is loaded with a substance selected from the group consisting of an agent and a nucleic acid.
  • the agent that the virus-like particle is loaded with preferably is a cytostatic and/or cytotoxic agent as disclosed above.
  • the nucleic acid that the virus-like particle is loaded with preferably is a nucleic acid as disclosed above.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, or the liposome of the second aspect, or the virus-like particle of the third aspect, and, optionally, a pharmaceutically acceptable carrier and/or excipient.
  • the present invention relates to the compound of the first aspect, or the liposome of the second aspect, or the virus-like particle of the third aspect, or the pharmaceutical composition of the fourth aspect for use in the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in an animal or a human subject.
  • a disease characterized by overexpression of fibroblast activation protein (FAP) is selected from the group consisting of cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorder.
  • the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocellular carcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymus carcinoma, desmoid tumors, glioma, astrocytoma, cervix carcinoma and prostate cancer.
  • the cancer is breast cancer, colon cancer, lung cancer, head and neck cancer, liver cancer or pancreatic cancer. Even more preferably, the cancer is colon cancer.
  • the chronic inflammation is selected from the group consisting of rheumatoid arthritis, osteoarthritis and Crohn’s disease.
  • the chronic inflammation is rheumatoid arthritis.
  • the fibrosis is selected from the group consisting of pulmonary fibrosis, such as idiopathic pulmonary fibrosis and liver cirrhosis.
  • the tissue remodeling occurs after myocardial infarction.
  • FAP fibroblast activation protein
  • the disease characterized by overexpression of fibroblast activation protein is a keloid disorder
  • the keloid disorder is selected from the group consisting of scar formation, keloid tumors and keloid scar.
  • the present invention relates to a kit comprising or consisting of the compound of the first aspect, or the liposome of the second aspect, or the virus-like particle of the third aspect, or the pharmaceutical composition of the fourth aspect and instructions for the treatment of a disease.
  • the disease is a disease as specified above.
  • Radioiodine labeled FAPI-01 was obtained via an organotin stannylated precursor, which was prepared through palladium catalyzed bromine/tin exchange.
  • FAPI-02 is a precursor for the chelation of radio metals which was synthesized in five steps.
  • Radioiodinations of the stannylated precursor were performed with peracetic acid.
  • For chelation with Fu-l77 and Ga-68 the pH of the reaction mixture was adjusted with sodium acetate and heated to 95 °C for 10 min. Stability in human serum was analyzed by precipitation and radio-HPLC analysis of the supernatant.
  • Scheme 1 depicts the initial synthesis of FAPI-01 which was achieved by performing a Br/Li- exchange with n-butyllithium at 5-bromoquinolie-4-carboxylic acid (3) and quenching with elemental iodine to obtain iodoquinoline 4.
  • This compound was coupled to the Gly-Pro-CN fragment by HBTU/HOBt-activation to provide non-radioactive reference material of F API-01 (1) ⁇
  • the stannylated precursor 6 was obtained by palladium-catalyzed stannylation of inhibitor 5 in dioxane at 80°C (Scheme 2).
  • the chelator DOTA was chemically linked to the basic scaffold of the FAP-inhibitor.
  • a bifunctional linker was attached to the hydroxyl group of 8 via an ether linkage, leading way to the synthesis shown in Scheme 3.
  • Ready available l-bromo-3-chloropropane was chosen to create a spacer, which is unharmed during the saponification of the simultaneously formed ester bond at the end of the one-pot-process.
  • Reverse-phase high-performance liquid chromatography was conducted using linear gradients of acetonitrile in water (0-100% acetonitrile in 5 min; 0.1% TFA; flowrate 2 mL/min) on a Chromolith Performance RP-l8e column (100 x 3 mm; Merck KGaA Darmstadt, Germany). UV-absorbance was detected at 214 nm. An additional g-detector was used for the HPLC-analysis of radioactive compounds.
  • HPLC-MS characterization was performed on an ESI mass spectrometer (Exactive, Thermo Fisher Scientific, Waltham, MA, USA) connected to an Agilent 1200 HPLC system with a Hypersil Gold C18 1.9 pm column (200 x 2.1 mm; 0- 100% acetonitrile in 20 min; flowrate 200 pL/min).
  • Analytical Radio-HPLC was performed using a Chromolith Performance RP-l8e column (l00> ⁇ 3mm; Merck; 0-30% acetonitrile in 10 min; flowrate 2 mL/min).
  • HPLC-purifications were performed on a LaPrep Pl lO-System (Knauer, Berlin, Germany) and a Reprosil Pur 120 column (Cl8-aq 5 pm 250 x 25mm; Dr. Maisch, Ammerbuch-Entringen, Germany).
  • the water/acetonitrile-gradient (15 or 25 min; 0.1% TFA; flowrate 20 mL/min) was modified for the individual products.
  • Radioligand binding studies were performed using HT-1080-FAP cells.
  • the radiolabeled compound was added to the cell culture and incubated for different time intervals ranging from 10 min to 24 h.
  • Competition experiments were performed by simultaneous exposure to unlabeled (10 5 M to lO 9 M) and radiolabeled compound for 60 min.
  • radioactive medium was removed after incubation for 60 min and replaced by non-radioactive medium for time intervals ranging from 1 to 24 h.
  • surface bound activity was removed by incubating the cells with 1 M glycine -HC1 buffer for 10 min. The radioactivity was measured using a g-counter, normalized to 1 mio cells and calculated as percentage of applied dose (%ID).
  • HT- 1080-FAP and HEK muFAP cells were seeded on uncoated coverslips in a 24-well plate and cultivated in culture medium containing 10% fetal calf serum to a final confluence of approx. 80-90%. The medium was removed and cells were washed with 0.5 mL PBS pH 7.4 for 2 times. FAPI-02-Atto488 (20 mM in DMEM) was added to the cells and incubated for 2 hrs at 37°C. Cells were washed with 0.5 mL PBS pH 7.4 for 3 times and fixed with paraformaldehyde (2% in PBS) for 15 min.
  • the overgrown coverslips were placed on microscope slides using mounting medium containing DAPI for cell nucleus staining (Fluoroshield, Sigma- Aldrich). Images were acquired on a laser scanning confocal microscope (Zeiss LSM 700; Zeiss, Oberkochen, Germany) using the Zeiss Plan-Apochromat 63x/l .4 Oil DIC III immersion objective at xy pixel settings of 0.099 x 0.099 pm and 1 Airy unit pinhole size for each fluorophore used (488 nm for FAPI-02-Atto488, 405 nm for DAPI). The pictures were processed consistently using the ZEN 2008 software and ImageJ.
  • F API-02 shows enhanced binding and uptake to human FAP-a as compared to FAPI-01.
  • FAPI-02 internalizes rapidly into FAP-a expressing cells (20.15 ⁇ 1.74 %ID after 60 min, of which 96 % internalized; Figure 1B), showing more stable and higher uptake rates in the course of time. Compared to the binding of F API-01 after 10 min of incubation, only 5 % of the activity remains after 24 h. In contrast, 34 % of the initial radioactivity of FAPI-02 is detected after 24 h of incubation. Efflux experiments demonstrate that FAPI-02 gets eliminated significantly slower than FAPI-01 , showing retention of 12 % of the originally accumulated radioactivity after 24 h (FAPI-01 1.1 % ID after 24 h; Figure 1E).
  • MTT is a tetrazolium dye which gets reduced by cellular enzymes resulting in the formation of the insoluble purple dye formazan.
  • the amount of the formed dye can be quantified by UV spectroscopy and reflects the number of viable cells present.
  • HT-1080-FAP cells are seeded in culture medium (DMEM containing 10% fetal calf serum) in 96-well plates and grown for two days to a final confluence of 80-90%.
  • the culture medium is removed and the cells incubated with FAPI-02-Dox and unconjugated Doxorubicin, which serves as a positive control, for 1 to 3 days at 37°C. Both compounds are added in culture medium in six different concentrations (0.1, 1, 10, 100, 1000, 10000 nM resp.). After incubation the medium is removed, MTT added in a final concentration of 0.5 mg/ml and incubated for 3 h at 37°C. After removing the dye solution, DMSO is added and incubated for 30 min in the dark to dissolve the dye crystals. Cell viability is determined by measuring absorption at 560 nm using a plate reader (Tecan Group Ltd., Mannedorf, Switzerland).
  • Tissue explants (as described previously in Halama et al., Cancer Cell, 2016) are being used for characterization of the invention. Histology for whole slide quantification of immune cells and measurements of cytokines within tissues are used to evaluate the invention. Enhanced infiltration rates of immune cells and modulation of the microenvironment are observed for all embodiments of the invention.

Abstract

La présente invention concerne un composé, un liposome comprenant ledit composé, une particule de type viral comprenant ledit composé, une composition pharmaceutique comprenant ou consistant en ledit composé, ledit liposome ou ladite particule de type viral, un kit comprenant ou consistant en ledit composé, ledit liposome, ladite particule de type viral ou ladite composition pharmaceutique et l'utilisation du composé, du liposome, de la particule de type viral ou de la composition pharmaceutique dans le traitement d'une maladie caractérisée par la surexpression de la protéine d'activation des fibroblastes (FAP).
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WO2021155288A1 (fr) * 2020-01-31 2021-08-05 Philip Stewart Low Thérapie antifibrotique dirigée sur une protéine d'activation des fibroblastes (fap)
WO2021160825A1 (fr) 2020-02-12 2021-08-19 Philochem Ag Ligands de protéine d'activation des fibroblastes pour applications d'administration ciblée
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WO2021224438A1 (fr) 2020-05-07 2021-11-11 Institut Curie Antxr1 comme biomarqueur de populations de fibroblastes immunosuppresseurs et son utilisation pour prédire la réponse à l'immunothérapie
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CZ309380B6 (cs) * 2020-03-30 2022-10-26 Ústav organické chemie a biochemie AV ČR v. v. i Sloučeniny pro inhibici fibroblastového aktivačního proteinu
CN115368342A (zh) * 2022-08-24 2022-11-22 西南医科大学附属医院 成纤维细胞活性蛋白抑制剂、其放射性核素标记物及制备方法和应用
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US11739076B2 (en) 2021-10-28 2023-08-29 Institute Of Nuclear Energy Research Atomic Energy Council, R.O.C. Compound or its salt thereof targeting fibroblast activation protein, its preparation methods and its uses thereof
CN116874545A (zh) * 2023-09-07 2023-10-13 山东第一医科大学(山东省医学科学院) 偶联药物及其制备方法与在制备治疗类风湿关节炎滑膜药物中的应用
US11872291B2 (en) 2016-12-14 2024-01-16 Purdue Research Foundation Fibroblast activation protein (FAP)-targeted imaging and therapy
WO2024052333A1 (fr) 2022-09-06 2024-03-14 Philochem Ag Ligands multivalents de protéine d'activation des fibroblastes pour applications d'administration ciblée
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